ACC 2007: When drugs can do more harm than good.
The results of two large randomised, placebo controlled drug trials, announced at the recent American Heart Association (AHA) meeting in Orlando, FL, have disappointed with excess mortality in the active treatment group. Both beta-blockers and drugs that raise HDL-cholesterol would have been expected to reduce cardiovascular events in patients at risk.
Although peri-operative betablockade has been shown to reduce cardiovascular deaths and myocardial infarction (MI) in very high-risk patients undergoing vascular surgery, these findings have not been extended to patients at lower risk. Indeed previous small trials, such as PeriOperative Beta-BLockadE (POBBLE – Journal of Vascular Surgery. 2005 Apr;41(4):602-9), suggested that there was no benefit.
The PeriOperative ISchemic Evaluation (POISE) trial was poised to extend the benefits of peri-operative beta-blockade to all patients, with increased cardiovascular risk, undergoing major non-cardiac surgery, including vascular surgery. Over 8,000 patients were enrolled in five continents over a five-year period (2002- 2007) and randomised to receive either metoprolol or placebo from a few hours before surgery until 30 days after surgery. Almost half of the 8,000 patients were undergoing major infrarenal vascular surgery. Although the frequency of the primary outcome measure (a composite of fatal and non-fatal cardiovascular events) was marginally lower in the metoprolol group (crude HR 0.88,p=0.04), this was driven by the very large reduction in non-fatal myocardial infarctions (HR 0.7, p=0.007). Operative mortality (30 days) was higher in the metoprolol group (HR 1.88 p=0.3) as was the number of disabling strokes (two-fold increase), p=0.005. This latter finding was backed up in a meta-analysis which included previous beta-blocker trials. Among the deaths there was an excess of deaths from sepsis in the metoprolol arm, which poses the question: did the use of metoprolol mask the early signs of sepsis such as unexplained tachycardia? Whilst the doses of metoprolol used might be considered by some to be heroic, 100mg twice daily, the findings of this trial cannot support the widespread use of peri-operative betablockade for vascular surgery patients. From the patient’s perspective, a reduction in risk of non-fatal MI would not offset the increased risk of stroke or death. The drugs in this trial were supplied by Astra Zeneca, but the loss to them from supplying this cheap, now long off patent, drug were minimal.
In addition, the results from the PROVIDENCE-1 clinical trial, which evaluated the effect of rifalazil in the treatment of intermittent claudication, associated with peripheral arterial disease (PAD), demonstrated that treatment for two months with the experimental antibiotic rifalazil did not result in a significant improvement in walking distance, claudication onset times, or other clinically-relevant parameters of PAD. The results were presented by the Chair of the trial’s Steering Committee, Dr Michael Jaff, assistant professor of Medicine Harvard Medical School Director, Vascular Medicine, Massachusetts General Hospital, MA, the trial was designed to test the hypothesis that eradication of any active Chlamydia pneumoniae infection in patients with intermittent claudication would improve walking. The prospective, randomised, doubleblinded international study was done on an outpatient basis with the primary endpoint being a change in baseline peak walking time, comparing those given Rifalazil against those given a placebo. Rifalazil, which selectively targets bacterial RNAse 2, was given in a single dose of 25mg once a week for eight weeks. The trial was well conducted and adequately powered to show an 18% increase in peak walking time (treadmill test) at six months. Only patients with high IgG titres against Chlamydia pneumoniae were selected and these patients had stable intermittent claudication with mean ankle/brachial pressure indices of 0.63. In total 297 patients (40-80 years old) were randomised, 153 to Rifalazil and 144 to placebo. After six months the peak walking time had increased by 20% in the Rifalazil group and 16% in the placebo group, a non-significant difference. Similarly, there were no differences in quality of life between the two randomised groups at six months. This is a disappointing result and it can be inferred that Chlamydia pneumonia infection may not play a significant role in occlusive peripheral arterial disease. “The conclusive data obtained from this well-powered and well-executed study provides a compelling argument that C. pneumoniae does not play a role in PAD that is modifiable by antibacterial therapy. Walking impairment in PAD patients remains a significant unmet medical need, but anti-chlamydial therapy does not appear to be the solution,” commented Jaff.